"Self-injurious behavior" (SIB) refers to acts which are usually highly repetitive in character and which result in direct physical damage to the individual. SIB is a significant problem. At the Lanterman State Developmental Center in Pomona, California, SIB occurs daily in fully 14% of the resident population. SIB restricts the affected person from educational and social opportunities and can restrict placement to institutional settings. It is estimated that the annual care for a single individual with SIB approaches $100,000 while cost to the nation of the twenty thousand afflicted individuals exceeded three billion dollars in 1988. We will focus on the pathogenesis and treatment of self-injurious behavior in the developmentally disabled. With a two-fold aim of establishing and examining appropriate models of this behavior, and of careful clinical study of a large population of developmentally disabled individuals who engage in frequent SIB. The hypothesis to be tested can be summarized: Pre-Clinical Studies: The serotonin agonist m-chlorophenylpiperazine (mCPP) will increase rat plasma adrenocorticoptopic hormone (ACTH). This neuroendocrine response will be differentially modified by the chronic administration of serotonergic agonists and antagonists. Pharmacological or surgical induction of self-injury will also modify the neuroendocrine response to mCPP. SIB in these models will be altered or acutely prevented by short-term treatment with some 5-HT antagonists; however, long-term treatment with 5-HT agonists, particularly buspirone or mCPP, or with re-uptake blockers like fluoxetine or sertraline will also attenuate SIB in these systems. Clinical studies: Some patients with self-injurious behavior will demonstrate functional differences in response to specific neuroendocrine challenge when compared to developmentally disabled and to normal controls. Following chronic treatment with the serotonergic agents buspirone and fluoxetine, the functional response to these neuroendocrine challenges will be altered both in normal volunteers and in a subgroup of individuals with SIB.